CN102481196B - Transferring nano-encapsulated drug through medical devices - Google Patents

Transferring nano-encapsulated drug through medical devices Download PDF

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Publication number
CN102481196B
CN102481196B CN201080028608.5A CN201080028608A CN102481196B CN 102481196 B CN102481196 B CN 102481196B CN 201080028608 A CN201080028608 A CN 201080028608A CN 102481196 B CN102481196 B CN 102481196B
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nano
carrier
drug delivery
implanted drug
delivery medical
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CN102481196A (en
Inventor
M·杜什
D·希尔迪瓦拉
P·索吉特拉
A·维亚斯
P·甘地
Z·V·P·莫西
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Envision Scientific Pvt Ltd
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Envision Scientific Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
    • A61F2/958—Inflatable balloons for placing stents or stent-grafts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M29/00—Dilators with or without means for introducing media, e.g. remedies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B9/00—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00
    • B32B9/04—Layered products comprising a layer of a particular substance not covered by groups B32B11/00 - B32B29/00 comprising such particular substance as the main or only constituent of a layer, which is next to another layer of the same or of a different material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Anesthesiology (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A drug-delivering insertable medical device for treating a medical condition associated with a body lumen is disclosed. The drug-delivering insertable medical device includes an outer surface coated with two or more nano-carriers having two or more average diameters. A nano-carrier of the two or more nano-carriers has an average diameter suitable for penetrating one or more layers of two or more layers of the body lumen. The nano-carrier includes a drug surrounded by an encapsulating medium. The encapsulating medium includes one or more of a biological agent, a blood excipient, and a phospholipid.

Description

The implanted drug delivery medical device of nano-carrier coating
Invention field
The present invention relates in general to armarium medicine being given body cavity and hit position.More specifically, the present invention relates to the implanted drug delivery medical device of the nano-carrier coating with one or more medicines, for effectively sending one or more medicines described through each layer of blood vessel.
Background of invention
Support and other armarium in Interventional Cardiology method is as percutaneous transluminal coronary angioplasty for rebuilding the suitable blood flow in obstructing arterial.But, existing Interventional Cardiology method and for the cardiology armarium of these methods all along with such as restenosis phenomenon.In order to there is the situation of restenosis after reducing angioplasty procedures or stentplacement, usually use bracket for eluting medicament (DES).Existing DES together loads with medicine under the assistance of polymer.Inflammation is caused in the position that described polymer can be implanted at DES.In some cases, owing to there is polymer in DES, the inflammation that the inflammation that DES causes may cause than bare metal support is more serious.Because the physiologic immunity response of body, the inflammation that described polymer causes can cause disease bolt to be formed then.The sick bolt of such formation can be acute disease bolt or subacute disease bolt.This sick bolt may aggravate to cause obstruction of artery further.In addition, relevant with the inflammatory reaction in later stage containing the DES of non-degradable polymer, thus cause sick bolt formation in late period.Therefore, restenosis may be caused for loading described medicine to the polymer on DES.
In order to avoid loading described medicine to the relevant inflammation of the polymer on described support to using, described medicine can be loaded into described support surface and without polymer.But, the described medicine of loading known in the art to described rack surface need not the method for described polymer be surface based on modifying described support.
In addition, compared with described bare metal support, one or more medicines and the described polymer that are present in the inner surface of described support cause the healing of damage postpone or cure improper.Usual suggestion healing postpones or cures inappropriate patient to carry out Long-term Anti platelet (as clopidogrel) treatment.Described Antiplatelet therapy is also relevant with side effect, is not therefore suitable for long-term.
In addition, what the particle size of the described medicine of coating on DES and described polymer was greater than target position organizes hole dimension.Therefore, high amount of drug is not still absorbed.Unabsorbed medicine can be flushed away and can have side effects in blood flow.Such as, the DES of current use loads with the medicine being greater than 100 micrograms, and wherein only 12 nanogram-25 nanogram medicines penetrate described arterial tissue.Remaining described medicine washes away from the inner surface of DES or discharges along with the time in blood flow.
In addition, the DES of current use is associated with the phenomenon of such as center restenosis and edge restenosis.The one of the main reasons of center restenosis is that the some parts of described damage fully can obtain the medicine of DES and the some parts (not covering the region of DES) of described damage obtains medicine that is considerably less or that do not have DES.With obtain compared with damaged portion that is considerably less or that there is no medicine, the damaged portion that fully can obtain described medicine may lessly be tended to restenosis occurs.
In existing DES, described drug coating is on described metal surface.The medication amount arriving described damage is generally equal to metal and tremulous pulse ratio.The described tremulous pulse of existing DES and metal than general range be 10%-20%. therefore, only the damage of 10%-20% can obtain described medicine.But the damage of residue 80%-90% obtains considerably less medicine or there is no medicine.In addition, because the drug particle size of surface coatings DES is comparatively large, described medicine does not realize optimal diffusion in arterial tissue.The character of described medicine is also relied in described drug diffusion to arterial tissue.Such as, due to the low solubility of sirolimus, it is poor to the diffusion in arterial tissue that sirolimus-eluting stents shows sirolimus.Therefore, sirolimus-eluting stents can show the high center restenosis to total restenosis 71%.But Paclitaxel-Eluting can show the high center restenosis to total restenosis 56%.In addition, existing DES is used to have lower affinity for native hydrophobic with body tissue to the most drug that gives patient.Therefore, a large amount of described medicine needs to be loaded in DES to realize required therapeutic effect.
Therefore, this area needs the implanted drug delivery medical device improved, make it to have the center restenosis of less situation, edge restenosis, total restenosis, acute disease bolt formed, subacute disease bolt is formed, late period sick bolt formed, damage cures and postpones and damage inappropriate treatment.In addition, this area needs the implanted drug delivery medical device improved, and it can reduce advises curing delay to damage after described DES placement and/or damaging the Antiplatelet therapy time of curing unsuitable patient originally.In addition, this area also needs the drug release therapeutic equipment improved, and it is for the blood vessel injury part maximization improving the bioavailability of described medicine, the biocompatibility improving medicine and send to make acquisition optimal drug load.
Brief Description Of Drawings
Fig. 1 shows the size distribution with the granulesten nano-particle of Malvern ZS90 detection in embodiment 1.
Fig. 2 shows the size distribution with the nano-carrier of Malvern ZS90 detection in embodiment 1.
Fig. 3 shows the chromatogram of embodiment 2 Plays solution.
Fig. 4 shows the chromatogram of sample solution in embodiment 2.
Fig. 5 shows the chromatogram of nano-carrier aqueous solution in embodiment 3.
Fig. 6 to show in embodiment 4 the sirolimus percentage ratio that the 1st day-discharges for 39 days from described coated stent system.
Detailed Description Of The Invention
Describe in detail according to the embodiment of the present invention, it should be noted that described embodiment main with treat about the armarium assembly of the medical symptom of body cavity combines.Therefore, the assembly described only comprises relevant those details understanding embodiment of the present invention, thus do not hinder apparent to those of ordinary skill in the art, have and describe the open in detail of advantage herein.
Herein, term " comprises ", " comprising " or its arbitrarily other modification be intended to cover non-exclusive comprising, make to comprise the process of a column element, method, article or device and not only comprise these elements but also other element that clearly do not list or that these processes, method, article or device are intrinsic can be comprised.Before have the element of " comprising ... " not get rid of (not more limit) other identical elements in containing the process of this element, method, goods or device.
In addition, describing in detail according to the embodiment of the present invention, all identical meanings for describing Science and Technology term of the present invention with those skilled in the art's understanding herein should being noted.
In addition, describe in detail according to the embodiment of the present invention, should notice that implanted drug delivery medical device can be and can insert or implant endoceliac medical treatment device to deliver drugs into the target position of described body cavity.Described implanted drug delivery medical device can be such as support, air bag, one of the support (tightening support in advance) and balloon catheter be contained on air bag.Described implantable drug delivery medical device can be any other armarium for puncture shaping surgery, and the nano-carrier of described medicine can be delivered to described target position and not deviate from scope of the present invention by it.
Described support can be such as endovascular stent, peripheral blood vessel support, urethra rack, prostate bracket, stent graft, Permanent implantation support, interim implant frame, with the support be made up of one or more (but being not limited to) metal, alloy, biodegradable polymer and non-degradable polymer, SS316L, L605 cobalt-chromium alloy and Ni-Ti alloy, and be surrounded by one of any support of described medicament nano carrier.In addition, described support can be any support being surrounded by one or more (but being not limited to) biodegradable polymer, biofacies same sex polymer, bioerodible polymer and non-degradable polymer.
Described air bag can be any air bag of being made up of elastomeric material, described air bag can expand with suitable expanding method in described puncture shaping surgery and available described medicament nano carrier coating to send the target position of two or more nano-carrier to described body cavity.Described air bag can be one of such as Angioplasty balloons and any other air bag for Interventional cardiovascular method.
Described pre-deflation support can be contained in support on air bag thus this support is contained on described air bag time described pre-deflation available described medicament nano carrier coating.Described pre-gauffer support also can comprise two or more described air bag, support, axle and the hypotube be contained on described air bag.
In addition, described implanted drug delivery medical device can be such as spinal implant, percutaneous implant, transdermal drug delivery equipment, dental implant, any surgical implant and can insert used inside human body in sending the armarium one of of one or more medicines to human body particular location.
It should be noted that, hereinafter the nano-carrier of described medicine also can refer to one or more nano-carriers, first group of nano-carrier, second group of nano-carrier, the 3rd group of nano-carrier and two or more nano-carrier.
Generally speaking, according to various embodiment, a kind of implanted drug delivery medical device being used for the treatment of the medical conditions relevant with body cavity is disclosed.Described medical conditions can be one of speckle accumulation in restenosis, body cavity obstruction, arthritis, myocardial infarction and described body cavity.Described body cavity can be such as blood vessel, urethra, esophagus, ureter and bile duct.
Described implanted drug delivery medical device comprises the outer surface with two or more nano-carrier coatings.When described implanted drug delivery medical device expands or expands on described target position, the outer surface of this implanted drug delivery medical device directly contacts described endoceliac target position.The nano-carrier of described two or more nano-carrier comprise be embedded medium around medicine.Due to described medicine by described embedding medium around, the surface of described nano-carrier does not have described medicine.Described embedding medium comprises one or more biological reagents, blood excipient and phospholipid.Described two or more nano-carrier has two or more mean diameter.Nano-carrier in described two or more nano-carrier has one or more layers the mean diameter being suitable for penetrating two-layer or more the described body cavity of layer.When described implanted drug delivery medical device is near described endoceliac target position, described two or more nano-carrier discharges from outer surface.Then, the nano-carrier in described two or more nano-carrier penetrates one or more layers of two-layer or more the described body cavity of layer based on mean diameter.Therefore, size-dependent nano-carrier is achieved through one or more layers of two-layer or more the described body cavity of layer.
In one embodiment, described implanted drug delivery medical device is used to treat the medical conditions relevant with blood vessel.Described blood vessel can be such as coronary artery, peripheral arterial, carotid artery, renal artery, iliac artery, one of inferior genicular artery and vein.Described blood vessel comprises two-layer or more the layer of described tissue.Two-layer or more the layer of described tissue comprises theca interna, intermediate layer and theca externa.Described theca interna comprises directly contact through vascular tissue's innermost layer of the blood flow of described blood vessel.Described intermediate layer comprises the vascular tissue's layer below described theca interna.And described theca externa comprises the vascular tissue's layer below described middle rete.
The outer surface of described implanted drug delivery medical device is by two or more nano-carrier coating.In an illustrative embodiments, when pre-tighten support be used as described implanted drug delivery medical device time, described outer surface as described in pre-deflation support one or more luminal surface part and by as described in one or more cell parts of exposing of pre-deflation support by two or more nano-carrier coating.According to different embodiment, described implanted drug delivery medical device only outer surface by two or more nano-carrier coating.And the inner surface of described implanted drug delivery medical device does not have described two or more nano-carrier substantially.Therefore, in an illustrative embodiments, when described implanted drug delivery medical device is support, then only described support luminal surface by two or more nano-carrier coating.And the surface of internal cavity of described support does not have described two or more nano-carrier substantially.The situation that this selectivity coating of described outer surface can make delay cure minimizes.
Therefore, when described drug delivery medical device is near described blood vessel, the nano-carrier of two or more nano-carrier can based on the mean diameter of described nano-carrier through theca interna, described middle rete and described theca externa described in one or more layers.Nano-carrier comes through theca interna, described middle rete and described theca externa described in one or more layers by penetrating hole, described middle rete relevant vascular parietal vessel and described theca externa relevant vascular parietal vessel between one or more tissues of being present on described theca interna.Be present in hole between the one or more tissues on described theca interna, described middle rete relevant vascular parietal vessel and described theca externa relevant vascular parietal vessel and there is different internal diameters.Therefore, the nano-carrier in described two or more nano-carrier penetrates theca interna described in one or more layers, described middle rete and described theca externa based on the mean diameter about described nano-carrier.
The two or more nano-carriers of described drug delivery medical device surface coatings have two or more mean diameter.Described two or more mean diameter can be 1nm-5000nm.
In one embodiment, described drug delivery medical device can be surrounded by first group of nano-carrier, second group of nano-carrier and the 3rd group of nano-carrier.Described first group of nano-carrier has the first mean diameter, is suitable for hole between the tissue by being present on described theca interna and penetrates described theca interna.Described second group of nano-carrier has the second mean diameter, is suitable for by described middle rete relevant vascular parietal vessel and is present on described theca interna between tissue hole and penetrates described middle rete.Described 3rd group of nano-carrier has the third mean diameter, is suitable for hole between the tissue by being present on described theca interna, described middle rete relevant vascular parietal vessel and described theca externa relevant vascular parietal vessel and penetrates described theca externa.
In one embodiment, the first mean diameter described can be 800nm-1500nm, and described the second mean diameter can be 300nm-800nm, and the third mean diameter described can be 10nm-300nm.In another embodiment, the first mean diameter described is 1000nm, and described the second mean diameter is 700nm, and the third mean diameter described is 200nm.The first mean diameter described, described the second mean diameter and the third mean diameter alterable described do not deviate from scope of the present invention to meet concrete treatment needs.
The described two or more nano-carrier of described drug delivery medical device coating can to comprise described in 10%-60% the 3rd group of nano-carrier described in second group of nano-carrier described in first group of nano-carrier, 20%-60% and 30%-80%.Or, can two or more nano-carrier described in coating to comprise about the 3rd group of nano-carrier described in second group of nano-carrier described in first group of nano-carrier, 10%-85% described in 15%-90% and 5%-85%.
Therefore, when described drug delivery medical device is when the target position of described blood vessel, correspond to the described two or more nano-carrier of first group of nano-carrier, described second group of nano-carrier and described 3rd group of nano-carrier described in one or more from the outer surface release of this implanted drug delivery medical device.Then, the two or more nano-carriers discharged pass one or more layers blood vessel described based on the corresponding mean diameter about described two or more nano-carrier.Therefore the size-dependent achieving two or more nano-carrier penetrates.
Except the size-dependent of described two or more nano-carrier penetrates, the speed that nano-carrier discharges from the outer surface of described drug delivery medical device also controls by the assistance of described nano-carrier mean diameter.The nano-carrier that mean diameter is little is discharged rapidly by described drug delivery medical device.Therefore, when described target position, the 3rd group of nano-carrier is less than described second group of nano-carrier and described first group of nano-carrier from the time needed for described outer surface release from the time needed for described outer surface release.Therefore, described 3rd group of nano-carrier shows the speed discharging outer surface fast.And compared with the rate of release of described 3rd group of nano-carrier, described second group of nano-particle and described 3rd group of nano-particle show the lower speed discharging outer surface.
Once described two or more nano-carrier discharges and passes described one deck and multilamellar blood vessel, described medicine is just discharged in the theca externa of one deck or more, middle rete and theca interna from described two or more nano-carrier.Embedding medium discharges described medicine when dissolving.Therefore, achieve described medicine to discharge in the tissue of described target position.In addition, one or more nano-carriers penetrating described theca externa may remain in described theca externa for a long time.In other words, described theca externa can be used as the reservoir of described medicine, and described medicine can therefrom slow releasing for a long time.
In addition, described medicine also can diffuse through the described theca externa of one deck or more, described middle rete and described theca interna for a long time.In this case, the medicine diffusing through the described theca externa of one deck or more, described middle rete and described theca interna can provide long-term drug entities internal diffusion.Therefore, due in the tissue of described medicine release and described medicine organize internal diffusion, on target position, the damage of largest portion obtains described medicine.Therefore, compared with traditional DES, the probability of center restenosis reduces.
In addition, spread between the tissue due to release and described medicine in the tissue of long-term described medicine, the delay healing of target position damage drops to minimum with the situation of improper healing compared with traditional DES.Therefore, the Antiplatelet therapy that damage need be had to postpone the patient of healing and/or improper healing also can be down to minimum.
In addition, because described embedding medium comprises one or more biological reagents, blood excipient and phospholipid, described two or more nano-carrier shows the affinity organized described target position.This affinity contributes to, within a period of time, described two or more nano-carrier is effectively transferred to described target position from described implanted drug delivery medical device outer surface.Therefore, each described first group of nano-carrier, described second group of nano-carrier and described 3rd group of nano-carrier all discharge from described outer surface in a period of time substantially.Therefore, in a period of time, the outer surface of described implanted drug delivery medical device does not have described two or more nano-carrier substantially.In an illustrative embodiments, when described implanted drug delivery device is support, described support can become in 7-45 days after described target position is placed at described support does not have two or more nano-carrier substantially.In another illustrative embodiments, described support can become in 30 days after described stentplacement does not have two or more nano-carrier substantially
In addition, described embedding medium also keeps the surface of described nano-carrier without any free drug.This is conducive to being avoided direct contact the on described medicine and described implanted drug delivery medical device surface.In addition, the only target position tissue described in described medicament contact when described nano-carrier penetrates described blood vessel described in one or more layers and described embedding medium dissolves.Therefore, described medicine is prevented directly to be exposed to the surface of described target position tissue and described implanted drug delivery medical device.
Described medicine can comprise the nanocrystal of described medicine.The nanocrystal of described medicine can have the mean diameter of 1nm-5000nm.In addition, the nanocrystal of described medicine can have two or more different mean diameter.Or described medicine can be one or more nano-sized particles, nanosphere, liposome, Nano capsule, dendrimers and has any other similar medication form of nano-scale.Described medicine can be one or more (but being not limited to) antiproliferatives, antiinflammatory, antitumor agent, anticoagulant, anti-fiber agent, antithrombotic agents, antimitotic agent, antibiotic agent, anti-allergic agent and antioxidant, antiproliferative, estrogen, protease inhibitor, antibody, immunosuppressant, cytostatic agent, cytotoxic agent, calcium channel blocker, phosphodiesterase inhibitor, prostaglandin inhibitor, food supplement, vitamin, anti-platelet aggregation agent and genetically engineered epithelial cell.
Described medicine can be one or more such as (but being not limited to) sirolimuss, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein, heparin, 17 beta estradiols, rapamycin, everolimus, ethyl rapamycin, Zuo Tamosi, ABT-578, Pai Ermosi A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin and derivant thereof, mitomycin (miomycine), heparin sodium, low molecular weight heparin, heparinoid, hirudin, argatroban, Forskolin, vapiprost, prostacyclin, prostacyclin analogs, dextran, D-phe-pro-arg-chloromethyl ketone, dipyridamole, glycoprotein iib/iiia, lepirudin 023 ludon, bivalirudin, nifedipine, colchicine, lovastatin, sodium nitroprusside, suramin, serotonin blocker, steroid, thiol protease inhibitor, triazolo pyrimidine, nitric oxide or nitric oxide donors, superoxide dismutase, superoxide dismutase mimics, estradiol, aspirin, angiopeptin, captopril, cilazapril, lisinopril, Pemirolast Potassiu, alpha-interferon, biological activity RGD and any salt thereof or analog.
Described medicine by described embedding medium around.Described embedding medium can be one or more biological reagents, blood excipient and phospholipid.Or described embedding medium can be the one or more of one or more biological reagents, one or more blood excipient, one or more phospholipid and one or more excipient.Described biological reagent can comprise the nano-particle of described biological reagent.The nano-particle of described biological reagent can have the mean diameter of 1nm-5000nm.In addition, the nano-particle of described biological reagent can have two or more different mean diameter.Or described biological reagent can comprise one or more nano-sized particles, nanosphere, liposome, Nano capsule, dendrimers and have the described biological reagent of any other similar form of nano-scale.
Described biological reagent can be one or more (but being not limited to) pharmaceutical carriers, excipient, blood constitutent, the excipient being derived from blood, the phospholipid of natural generation, solid lipid nano-particles, available from the phospholipid of live animal, synthesis derivative phospholipid, lipoid, vitamin and glycan molecule.Described biological reagent can be such as (but being not limited to) steroid, vitamin, estradiol, esterified fatty acid, non-esterified fatty acid, glucose, inositol, Pfansteihl salt, lipoprotein, sugar, tricalcium phosphate, calcium phosphate precipitation, tri basic calcium phosphate, be derived from least one people, the material of egg and Semen sojae atricolor, phosphatidylcholine (phospholipon) 80H, phosphatidylcholine 90H, lipoid S75, lipoid E80, Intralipid (Intralipid) 20, lipoid EPC, lipoid E75, available from the lipid of egg, available from the lipid of Semen sojae atricolor, lecithin, phosphatidyl glycerol, phosphatidylinositols, Phosphatidylserine, phosphatidic acid, cuorin, PHOSPHATIDYL ETHANOLAMINE.
Described phospholipid can comprise the nano-particle of described phospholipid.The nano-particle of described phospholipid can have the mean diameter of 1nm-5000nm.In addition, the nano-particle of described phospholipid can have two or more different mean diameter.Or described phospholipid can comprise one or more nano-sized particles, nanosphere, liposome, Nano capsule, dendrimers and have the described phospholipid of any other similar form of nano-scale.Described phospholipid can comprise one or more (but being not limited to) lipid available from egg, the lipid available from Semen sojae atricolor, phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, Phosphatidylserine, phosphatidic acid, cuorin and PHOSPHATIDYL ETHANOLAMINE.
Described blood excipient can comprise the nano-particle of described blood excipient.The nano-particle of described blood excipient can have the mean diameter of 1nm-5000nm.In addition, the nano-particle of described blood excipient can have two or more different mean diameter.Or described blood excipient can comprise one or more nano-sized particles, nanosphere, liposome, Nano capsule, dendrimers and have the described blood excipient of any other similar form of nano-scale.Described blood excipient can be one or more (but being not limited to) steroid, vitamin, estradiol, esterified fatty acid, non-esterified fatty acid, glucose, inositol, Pfansteihl salt, lipid, lipoprotein, phospholipid, sugar, tricalcium phosphate, calcium phosphate precipitation and tri basic calcium phosphate
Described blood excipient and described biological reagent pH lower than 7.4 time solvable.Therefore, when described two or more nano-carrier contact described target position organize time, described biological reagent and described blood excipient dissolve in described blood.The dissolving of described biological reagent and described blood excipient causes described medicine to discharge from described two or more nano-carrier at described target position.Therefore the pH dependent release of the medicine of two or more nano-carrier is achieved.
In an illustrative embodiments, described implanted drug delivery medical device is coronary stent.Described coronary stent is such as chromium cobalt L-605 support.Described coronary stent comprises tube chamber (outward) surface with two or more nano-carrier coatings.Described two or more nano-carrier comprises the 3rd group of nano-carrier that mean diameter is about first group of nano-carrier of 1200nm, mean diameter is about 700nm second group of nano-carrier and mean diameter are about 200nm.When described support is near described target position, described two or more nano-carrier discharges from the luminal surface of described support.Then described first group of nano-carrier penetrates described theca interna by being present in hole between the tissue on described theca interna.Described second group of nano-carrier is by described middle rete relevant vascular parietal vessel and be present on described theca interna between tissue hole and penetrate described middle rete.Described 3rd group of nano-carrier is by described theca externa relevant vascular parietal vessel, described middle rete relevant vascular parietal vessel and be present on described theca interna between tissue hole and penetrate described theca externa.
In another embodiment, described implanted drug delivery medical device is air bag.Described air bag is such as ultra-thin Angioplasty balloons.Described air bag comprises the outer surface with two or more nano-carrier coatings.Described two or more nano-carrier comprises the 3rd group of nano-carrier that mean diameter is about first group of nano-carrier of 1200nm, mean diameter is about 700nm second group of nano-carrier and mean diameter are about 200nm.When described air bag expands after described target position, described two or more nano-carrier discharges from the luminal surface of described support.Then described first group of nano-carrier penetrates described theca interna by being present in hole between the tissue on described theca interna.Described second group of nano-carrier is by described middle rete relevant vascular parietal vessel and be present on described theca interna between tissue hole and penetrate described middle rete.Described 3rd group of nano-carrier is by described theca externa relevant vascular parietal vessel, described middle rete relevant vascular parietal vessel and be present on described theca interna between tissue hole and penetrate described theca externa.When described air bag be folding configuration or non-collapsible configuration time, described air bag can have described two or more nano-carrier by coating.
In another illustrative embodiments, described implanted drug delivery medical device is tighten support (being contained in the support on air bag) in advance.Such as, described pre-deflation support is the chromium cobalt L-605 support that ultra-thin Angioplasty balloons is housed.Described pre-deflation support coating has two or more nano-carrier.The nano-carrier of the described two or more nano-carrier of coating on described pre-deflation support comprises the sirolimus nanocrystal being embedded with one or more soybean phospholipids and tricalcium phosphate.Second group of nano-carrier that described two or more nano-carrier comprises first group of nano-carrier that mean diameter is 1200nm, mean diameter is 700nm and mean diameter are the 3rd group of nano-carrier of 200nm.
When described support is equipped with described air bag, the outer surface coating of described pre-deflation support has described two or more nano-carrier.The one or more parts (the one or more parts of the described air bag exposed by one or more poles of described support) that described air bag is not covered by described support also along with described support luminal surface together coating have described two or more nano-carrier.Because the surface of internal cavity of described support is covered by described air bag, so only the luminal surface coating of described support has described two or more nano-carrier.When described pre-deflation support is near described target position, described airbag inflation.The expansion of described air bag causes the expansion of described support.Respond to the expansion of the described air bag on described coronary artery target location and the expansion of described support, described two or more nano-carrier discharges from described precoating support.The described two or more nano-carriers of coating in the one or more parts of described air bag produce one or more nano-carriers described and release from the prominent of described air bag.And coating produces the controlled release of described two or more nano-carrier from described support luminal surface at the described two or more nano-carriers of described support luminal surface.
In addition, the outer surface of described pre-deflation support comprises the part of described air bag, and described part longitudinal extension exceeds one or more far-end border and the proximal boundary of described support.In this case, the part leaving the one or more far-end border of described support and the proximal boundary of described support with at least 0.05mm longitudinal extension also can have described two or more nano-carrier by coating.Can deliver drugs into by part described in described two or more nano-carrier coating the damage that the far-end border of described support and/or proximal boundary exist outward, described part exceeds the far-end border of described support and/or the proximal boundary of described support with at least 0.05mm longitudinal extension.Therefore, the minimizing possibility of the edge restenosis after stentplacement described in object can be made.
In another illustrative embodiments, tightening support (being contained in the support on air bag) coating in advance has two-layer or more the described two or more nano-carrier of layer.Skin in described two-layer or more the layer of coating on described air bag and described support comprises described 3rd group of nano-carrier.And the internal layer in described two-layer or more the layer of coating on described air bag and described support comprises the described first group of nano-carrier of one or more and described second group of nano-carrier.When described pre-deflation support is near described target position, be present in the burst release that described air bag and the outer field described 3rd group of nano-carrier of described support provide described 3rd group of nano-carrier.And be present in described second group of nano-carrier of one or more of described internal layer and described first group of nano-carrier produce one or more from described second group of nano-carrier of described pre-deflation support and the controlled release of described first group of nano-carrier.
In one embodiment, described implanted drug delivery medical device comprises the outer surface that coating has the two or more nano-carriers of two-layer or more layer.The two or more nano-carriers be present in the skin of described two-layer or more layer comprise first group of medicine.And the two or more nano-carriers be present in the internal layer of described two-layer or more layer comprise second group of medicine.Described second group of medicine can comprise one or more medicines different from one or more medicines existed in described first group of medicine.Described first group of medicine can comprise such as (but being not limited to) one or more antiinflammatories and antithrombotic agents.Be present in described outer field first group of medicine and can produce prominent releasing.Therefore, can by described first group of drug delivery to described target position to control the inflammation that can be caused by described implanted drug delivery medical device or damage.And described second group of medicine can comprise such as (but being not limited to) antiproliferative.The described second group of medicine be present in described internal layer discharges from described internal layer after described skin is released.Therefore, can second group of medicine described in chronotherapeutic delivery to control the proliferation period in described inflammatory cell cycle.
One or more described first group of medicine and described second group of medicine can be selected from one or more (but being not limited to) antitumor agents, anticoagulant, anti-fiber agent, antithrombotic agents, antimitotic agent, antibiotic agent, anti-allergic agent and antioxidant, estrogen, protease inhibitor, antibody, immunosuppressant, cytostatic agent, cytotoxic agent, calcium channel blocker, phosphodiesterase inhibitor, prostaglandin inhibitor, food supplement, vitamin, anti-platelet aggregation agent and genetically engineered epithelial cell, and do not deviate from scope of the present invention.
In another embodiment, described implanted drug delivery medical device is by the described two or more nano-carrier coatings of three layers.The innermost layer of two or three nano-carrier of described three layers comprises pretreat reagent.The intermediate layer of described three layers comprises antiproliferative and the outermost layer of described three layers comprises one or more antiinflammatories and antithrombotic agents.Described outermost layer provides described the prominent of two or more nano-carrier to release.Therefore, the outermost layer containing antiinflammatory described in one or more and antithrombotic agents can solve described inflammation.Intermediate layer containing described antiproliferative discharges described two or more nano-carrier after described outer field two or more nano-carrier release.Therefore, described intermediate layer can solve the proliferation period in the described inflammatory cell cycle being positioned at described target position.And described innermost layer discharges described two or more nano-carrier after the two or more nano-carrier releases in described intermediate layer.Therefore, the innermost layer containing described prophylactic/therapeutic agent can help lend some impetus to and form extracellular matrix at target position, therefore solves the regeneration period in described inflammatory cell cycle.Therefore, described implanted drug delivery medical device can be designed to solve each phase in the described inflammatory cell cycle being positioned at described target position.
Generally speaking, according to various embodiment, the invention also discloses the Therapeutic Method of the medical conditions relevant with body cavity.Described medical conditions can be restenosis, body cavity obstruction, arthritis, myocardial infarction and described endoceliac speckle accumulation.Described body cavity can be such as blood vessel, urethra, esophagus, ureter and bile duct.In one embodiment, described method comprises by using its outer surface coating to have the implanted drug delivery medical device of two or more nano-carrier to send the target position of two or more nano-carrier to described blood vessel.
Described method also comprises and being placed on the target position of described blood vessel by described implanted drug delivery medical device.Then described implanted drug delivery medical device expansion or expansion.As to expansion or the response of the described implanted drug delivery medical device that expands, target position described in the exterior surface of described implanted drug delivery medical device and described two or more nano-carrier discharge from described outer surface.Then, the two or more nano-carriers discharged based on the corresponding mean diameter about described two or more nano-carrier through one or more layers in described two-layer or more layer blood vessel.
The nano-carrier of described two or more nano-carrier comprise be embedded medium around medicine.Described encasement medium comprises one or more biological reagents, blood excipient, and phospholipid.According to each embodiment, described medicine can comprise the nanocrystal of described medicine.And described biological reagent, phospholipid and blood excipient can comprise the nano-particle of described biological reagent, phospholipid and blood excipient respectively.The nano-particle of the nanocrystal of described medicine, the nano-particle of described biological reagent, described phospholipid and the nano-particle of described blood excipient can be obtained by traditional method.Or also can use the nano-particle of the nano-particle of the nanocrystal of commercially available described medicine, described biological reagent, the nano-particle of described phospholipid and described blood excipient.Such as, the nano-particle of the nanocrystal of one or more described medicine, the nano-particle of described biological reagent, the nano-particle of described phospholipid and described blood excipient can use one or more (but being not limited to) high pressure homogenizing, spraying dry, high speed homogenisation, ball milling, pulverizing, sol-gel process, hydro-thermal method, spray heating decompositions etc. to obtain.
Nano-carrier is obtained by methods known in the art nanocrystal of medicine described in the nanoparticles embedded of biological reagent, described phospholipid, described blood excipient described in one or more.Obtain the mean diameter that nano-carrier can have 1nm-5000nm.
In one embodiment, the 3rd group of nano-carrier of first group of nano-carrier of described medicine of mean diameter 1200nm, second group of nano-carrier of the described medicine of mean diameter 700nm and the described medicine of mean diameter 200nm is obtained by one or more methods known in the art.In addition, the 3rd group of nano-particle of first group of nano-particle of described biological reagent of mean diameter 1200nm, second group of nano-particle of the described biological reagent of mean diameter 700nm and the described biological reagent of mean diameter 200nm is obtained by one or more methods known in the art.
Then, first group of nanocrystal solution of described medicine, second group of nanocrystal solution of described medicine and the 3rd group of nanocrystal solution of described medicine is obtained with suitable solvent.Similarly, first group of nanoparticles solution of described biological reagent, second group of nanoparticles solution of described biological reagent and the 3rd group of nanoparticles solution of described biological reagent is obtained with suitable solvent.
Then, first group of nanocrystal solution of described medicine and first group of nanoparticles solution of described biological reagent obtain first group of nano-carrier with the first mean diameter through embedding process.Similarly, second group of nanocrystal solution of described medicine and second group of nanoparticles solution of described biological reagent obtain second group of nano-carrier with the second mean diameter through embedding process.And the 3rd group of nanoparticles solution of the 3rd of described medicine the group of nanocrystal solution and described biological reagent obtains the 3rd group of nano-carrier with the 3rd mean diameter through embedding process.
Then by methods known in the art to obtained first group of nano-carrier, second group of nano-carrier and the 3rd group of nano-carrier coating, as one or more layers on described implanted drug delivery medical device outer surface.
In an illustrative embodiments, available suitable solvent obtains the solution of nano-carrier described in first group, the solution that is molten and nano-carrier described in the 3rd group of nano-carrier described in second group.Then, with coating machine known in the art by the solution coating of nano-carrier described in the solution of the solution of nano-carrier described in first group, nano-carrier described in second group and the 3rd group on the outer surface of described implanted drug delivery medical device.
Described coating machine can have rotatable mandrel.Described implanted drug delivery medical device can be equipped with rotatable mandrel and rotate along described rotatable mandrel.Under the outer surface of described implanted drug delivery medical device can be exposed to spray nozzle.Then, by the spray solution of nano-carrier described in the solution of the solution of nano-carrier described in one or more first group, nano-carrier described in second group and the 3rd group at described outer surface to obtain the described implanted drug delivery medical device that coating has described first group of nano-carrier, described second group of nano-carrier and described 3rd group of nano-carrier.
Described coating machine can have one or more reservoirs for storing the solution of nano-carrier described in the solution of nano-carrier described in first group, the solution of nano-carrier described in second group and the 3rd group.Such as, described in the solution of nano-carrier described in first group, the solution of nano-carrier described in second group and the 3rd group, the solution of nano-carrier can be stored in three kinds of different reservoirs.Or the solution of nano-carrier described in the solution of the solution of nano-carrier described in first group, nano-carrier described in second group and the 3rd group can be used as mixture and is stored in single reservoir.One or more reservoirs described can provide the solution of nano-carrier described in the solution of nano-carrier described in one or more first group, the solution of nano-carrier described in second group and the 3rd group to spray nozzle.Described spray nozzle can be used for the spray solution of the solution of the solution of nano-carrier described in first group, nano-carrier described in second group, nano-carrier described in the 3rd group on the surface of described implanted drug delivery medical device.
In another embodiment, two-layer as described implanted drug delivery medical device outer surface of two or more nano-carrier described in coating.On described outer surface, described implanted drug delivery medical device is prepared by spraying the such as solution of nano-carrier described in the 3rd group.Dry described implanted drug delivery medical device subsequently.Then, can by the spray solution of nano-carrier described in the solution of nano-carrier described in one or more second group and first group on described outer surface.Dry described implantable drug delivery medical device subsequently.Therefore, the described implanted drug delivery medical device with two layers of described two or more nano-carrier can be obtained.
Then, the described implanted drug delivery medical device of two or more nano-carrier there is is to insert described blood vessel coating with conduit assembling.Described conduit assembling can comprise wire, conduit, air bag, be contained in the support on described air bag and the expansion gear for the described air bag that expands.Described wire extends only to cross apart from a bit of distance of described target position in described blood vessel.The conduit then with described support and the air bag being contained in described distal end of catheter extend above described conduit, make the support be contained on described air bag be in described target position.Once the described support be contained on described air bag arrives the described target position in described blood vessel, to expand described air bag with described expansion gear.After described airbag inflation, the support be contained on described air bag also expands and contacts described blood vessel wall by described support at described target position and exposes the outer surface of described support and the part of described air bag.When described in described balloon contacts during target position, the described two or more nano-carrier of coating on described air bag discharges from described air bag and is delivered to described target position.Then, described air bag shrinks and returns from described blood vessel, and described support is stayed described target position.Support on described target position can for a long time at the described two or more nano-carrier of described blood vessel target position release.Then, the two or more nano-carriers discharged based on its relevant corresponding mean diameter through one or more layers in described two-layer or more layer blood vessel.
Under certain situation, described armarium can comprise the support be contained on air bag.Under the described support be contained on described air bag can be exposed to described spray nozzle and the spray solution of available described two or more nano-carrier.Therefore, the one or more parts (the one or more parts of the described air bag exposed by the pole of described support) that do not covered by described support of described air bag are also with described two or more nano-carrier coating.Described two or more nano-carrier is made to be discharged into described target position fast from described implanted drug delivery medical device by the one or more parts of the described air bag of described two or more nano-carrier coating.And coating makes described two or more nano-carrier from the outer surface delayed release of described implanted drug delivery medical device to described target position at the described two or more nano-carrier of described rack outer surface.
Embodiment 1:
Soybean phospholipid available from Lioid GMBH, batch number: 776114-1/906.Sirolimus opens up (Fujan) chemical company available from middle national wealth, and purity is higher than 99.5%.Water used, other solvents and reagent are HPLC level.Amazonia (being contained in the chromium cobalt coronary artery L-605 mounting system on Angioplasty balloons, " described mounting system " hereinafter) is available from transparent tile department (Minvasys) company of Paris, FRA.
Soybean phospholipid (20mg w/w) is joined (10ml) in deionized water and then adds Tween 80 (5mg) to obtain the aqueous solution of soybean phospholipid.The aqueous solution (10ml) of soybean phospholipid in ice-cold water-bath with 15000-20000rpm high speed homogenisation 20-25 minute to obtain solution A 1.Obtain solution A 1 nano-particle containing soybean phospholipid.The granular size using Malvern ZS90 (Britain Ma Erwen (Malvern) company) size detector to carry out described solution A 1 subsequently detects.Fig. 1 shows the size distribution of the granulesten nano-particle detected with Malvern ZS90.Find that the mean diameter of described soybean phospholipid nano-particle is 475.79nm.
Sirolimus (20mg w/w) is added in 10ml deionized water to obtain the aqueous solution of sirolimus.The aqueous solution (10ml) of sirolimus in ice-cold water-bath with 15000-20000rpm high speed homogenisation 150-200 minute to obtain solution A 2.Obtain solution A 2 nanocrystal containing sirolimus.The granular size using Malvern ZS90 (Ma Erwen company of Britain) size detector to carry out described solution A 2 subsequently detects.
By solution A 1 progressively (dropwise) to add in solution A 2 and with 15000-20000rpm high speed homogenisation 20 minutes to obtain 20ml solution A 3.Solution A 3 homogenizes 10 minutes again.Then magnetic stirring apparatus (India Ai Kumai Coase (Accumax) company, the attached agitator of 2MLH hot plate evaporators) agitating solution A320 minute is used.Obtain solution A 3 containing nano-carrier (by soybean phospholipid nano-particle around sirolimus nanocrystal).The granular size using Malvern ZS90 (Ma Erwen company of Britain) size detector to carry out described solution A 3 subsequently detects.Fig. 2 shows the size distribution of the nano-carrier detected with Malvern ZS90.Discovery mean particle size is 410nm.
Solution A 3 (aqueous solution of nano-carrier) uses dichloromethane extraction further.Solution A 3 (20ml) is transferred in 100ml separatory funnel.50ml dichloromethane is added in described 100ml separatory funnel.Gained mixture vibrates and then leaves standstill for 15 minutes.Observe two-layer subsequently in described 100ml separatory funnel, i.e. water layer and described dichloromethane layer.Described dichloromethane layer is separated with described water layer.Described dichloromethane layer and described nano-carrier solution store in the amber little measurement flask having lot number.Subsequently, the solution of described nano-carrier is used for mounting system described in coating.
Described nano-carrier solution (5ml) is loaded in the reservoir of coating machine.Described mounting system is contained in the rotary core shaft of described coating machine.Under described mounting system being exposed to the spray nozzle of described coating machine.By rotate described mandrel and rotate described mounting system with 5-40rpm and simultaneously with the inert gas pressure of 0.5-4.0 pound/square inch (psi) and 2 vibrations by described nano-carrier spray solution in described mounting system.Therefore the described mounting system (" described coated stent system " hereafter) with described nano-carrier coating is obtained.Remove described mounting system and under high resolution microscope, observe the flatness of described coating surface and any foreign particle.Then as coated stent system as described in analyzing further as described in embodiment 2 below.
Embodiment 2:
Detect the medicament contg of described mounting system
The sirolimus content be loaded in described coated stent system is calculated by HPLC analytic process.HPLC operating parameter is elected as: flow velocity is set to 1.2ml/ minute (± 0.01), λ maximum is set to 278nm (± 1nm), column temperature is set to 60 DEG C (± 2 DEG C), and detector sensitivity is set to 0.02AUFS, is set to 20 minutes analysis time.
The HPLC system [LC-10ATVP pump (Japanese hyracothere ancestral (SHIMADZU) company)] connecting UV-VIS detector [SPD-10AVP (Japanese hyracothere ancestral (SHIMADZU) company)] and Rheodyne integrator [analytical technology (Analytical Technologies) company analyzes (Analytical) 2010] is analyzed for HPLC.Post-C 18[RP18 long 4.6mm X 250mm, granular size 5 μm] joint pin incubator [PCI] is for heating.25 μ l Hamilton (Hamilton) micro-syringe are used for injected sample.Before analyzing, described sample Mi Libo (millipore) PTFE 0.45 um syringe filter filters to avoid any particle matter.Use pre-calibrated A level capacity bottle.By amber glassware with lucifuge.Thorough (Renchem) solvent of all sieve used in analysis and reagent are HPLC level.Use the sirolimus available from middle national wealth exhibition (Fujan) chemical company, purity is higher than 99.5%.
Mobile phase comprises the acetonitrile that concentration ratio is 45: 40: 15: methanol: water.Then mobile phase in ultrasonic washing unit degassed 10 minutes.
Sirolimus (0.5mg) is put into the 10ml canonical measure flask (SMF) of clean dried.Then with described movement, described SMF is filled to scale and the 5-10 minute that vibrates.Then described SMF keeps and degassed 10 minutes at ultrasonic washing unit.Then filter described solution with 0.45 um syringe filter and obtain the standard solution that " normal concentration " is 50 μ g/ml.
Standard solution described in 20 μ L to be injected in HPLC infusion appliance by described micro-syringe and to obtain the chromatogram of described standard solution.Fig. 3 shows the chromatogram of described standard solution.Calculate the peak area (" standard area ") of described standard solution subsequently.Find that the retention time of described standard solution is 3.732 minutes and finds to correspond to " standard area " of described standard solution peak value for 3196.970mV* second.
In order to the medicament contg that will be loaded in described mounting system is quantitative, prepare described sample solution by described coated stent system being inserted to be equipped with in the 10ml SMF of methanol (10ml).Then described SMF is kept in ultrasonic bath being dissolved completely in methanol to make the being present in intrasystem sirolimus of described coated stent for 10 minutes.Therefore, sample solution is obtained.
Sample solution described in 20 μ L to be injected in HPLC infusion appliance by described micro-syringe and to obtain the chromatogram of described sample solution.Fig. 4 shows the chromatogram of described sample solution.Calculate the peak area (" sample area ") of described sample solution subsequently.Find that the retention time of described sample solution is 3.470 minutes and finds to correspond to " sample area " of described sample solution peak value for 683.235mV* second.
The sirolimus content in described coated stent system is present in subsequently with following formulae discovery:
Medicament contg=(sample area/standard area) * (normal concentration/sample concentration)
Therefore, medicament contg=(683.235/3196.970) * (50/ (1/10))=106.82 μ g
Therefore, the medicament contg be loaded in described coated stent system is 106.85 μ g.
Embodiment 3:
Embedding efficiency (EE):
The aqueous solution (embodiment 1) of nano-carrier described in 1ml is loaded in 10ml SMF.Volume is adjusted to 10ml.The aqueous solution of 20 μ L nano-carriers to be expelled in HPLC infusion appliance and to obtain the chromatogram of nano-carrier aqueous solution.Fig. 5 shows the chromatogram of nano-carrier aqueous solution.Find that the retention time of nano-carrier aqueous solution is 4.308 minutes and " the nano-carrier aqueous solution area " that correspond to nano-carrier aqueous solution peak value is 280.555.Following formula is adopted to calculate free drug amount:
Free drug amount=(nano-carrier aqueous solution area/standard area) * (normal concentration/nano-carrier concentration of aqueous solution)
Therefore, free drug content (sirolimus)=(280.555/3196.970) * (50/ (1/10))=43.52.Therefore, the free drug amount of 1ml nano-carrier aqueous solution is 43.87 μ g.Therefore, the free drug amount existed in 20ml is 877.4 μ g.Subsequently, following formula is adopted to calculate described % embedding efficiency:
%EE=(medicine initial weight (mg)-medicine free amount (mg)) * 100/ (medicine initial weight (mg))
％EE＝(20-0.8774)*100/20＝95.61％
Therefore, % embedding efficiency is 95.61%.
Embodiment 4:
State the sirolimus release of coated stent system at pH 6.4 times external institutes with phosphate buffered saline (PBS) (PBS).Described PBS solution is prepared by dissolving 1.79g Phosphoric acid disodium dodecahydrate, 1.36g orthophosphoric acid hydrogen potassium and 7.02g sodium chloride in 1000ml hplc grade water.Described solution keeps 10 minutes to dissolve in ultrasonic washing unit.
The PBS of fresh preparation is respectively added in 3 1.5ml cylindrical bottle.Described three bottle called afters 15 seconds, 60 seconds and the 1st day.Described 15 seconds bottles, 60 seconds bottles and the 1st day bottle hatch 60 minutes at 37 DEG C (± 1 DEG C).
Then described coated stent system immerses described 15 seconds bottles and moves up and down 15 seconds.Then, described coated stent system is transferred in described 60 seconds bottles and is also expanded wherein.The support of described expansion keeps within 60 seconds, then exiting described 60 seconds bottles in described 60 seconds bottles.Subsequently, the 1st day bottle described in described coated stent system introducing be placed in incubator 24 hours.
PBS solution from described 15 seconds bottles, described 60 seconds bottles and described 1st day bottles is transferred in different separatory funnel.Equivalent methanol (5ml) is joined in all three separatory funnels, then adds dichloromethane (10ml).All three separatory funnels fully vibrate and then leave standstill for 10 minutes.Be separated the organic facies containing methanol, dichloromethane and sirolimus afterwards and analyze with HPLC.Similarly, by every day, described coated stent is assembled in respective markers bottle the coated stent assembling of hatching 24 hours to analyze the 2nd day to the 39th day.Measure the sirolimus content that is present in each bottle and calculate the sirolimus release in vitro percentage ratio of the 1st day to the 39th day.Fig. 6 shows the sirolimus percentage ratio that the 1st day-discharges for 39 days from described coated stent system.The medicine of loss is transported during within described 15 seconds, bottle represents angioplasty procedures.Described 60 seconds bottles represent prominent the releasing of the 1st day and the 2nd day bottle represents sirolimus from the procedural release described coated stent assembling to the 39th day bottle.Conclusion is at the end of the 39th day, about has the release from described coated stent assembling of 80% sirolimus.
Embodiment 5:
Select four kinds of animals.These four kinds of animals respectively implant 3 kinds of supports.Described three kinds of supports comprise described mounting system (two kinds) and a kind of mounting system without sirolimus.Analyze described implantation and QCA result subsequently, before providing implantation, implant Mean Lumen diameter that is rear and described support fragment after 28 days.Described QCA result is for calculating support/tremulous pulse ratio, described acquisition, shrinking percentage and rear wall losses at once.Describedly generally be about 1mm-1.5mm without the rear wall losses in sirolimus mounting system (BMS) situation.And the rear wall losses in described mounting system situation is 0.45mm (± 0.23mm).Do not have to report the death relevant with described mounting system.In addition, in any described four kinds of animals, the report thrombosis relevant with described mounting system or restenosis is not had.Therefore, conclusion is that described mounting system is effective and safe with compared with the mounting system of sirolimus or described BMS.In identical research, 28 days experiment display mean intimal thickness are about 150 (± 15) micron in DES, are about 185 (± 50) micron in excipient coated stent.Qualitative analysis is presented at inner membrance described in all sirolimus coated stent and cures completely.
The each embodiment of the present invention provides the implanted drug delivery medical device of the different average-size nano-carrier coatings with one or more medicines, and it is for effectively sending one or more medicines described through each layer of blood vessel.The present invention also provides the implanted drug delivery medical device showing and improve bioavailability and the biocompatibility of one or more medicines described, then only needs low dose of one or more medicines described to be loaded into described implanted drug delivery medical device.Is formed according to the edge restenosis of implanted drug delivery medical device of the present invention and less situation, center restenosis, total restenosis, subacute disease bolt, late period sick bolt formed, damage and cure that to postpone and damage inappropriate treatment relevant, these scripts are relevant to described existing DES.
Those skilled in the art will recognize that above-mentioned generally acknowledged advantage as herein described and other advantages are only exemplary, be not used to all advantages describing each embodiment of the present invention completely.
In the above specification, the specific embodiment of the present invention is described.But those of ordinary skill in the art can understand, various modifications and variations can be carried out when not departing from the scope of the invention described in following claims.Therefore, will be understood that description and accompanying drawing are illustrative, and nonrestrictive, and all such modifications are all included in the scope of the invention.Should not think these benefits, advantage, the scheme of dealing with problems, and any benefit, advantage or solution may be produced or make its more significant any key element be the key of any or all claim, needs or required feature or key element.The present invention is defined separately by appended claims, comprise this application and claim is proposed any amendment carried out of all equivalents unsettled period.

Claims (35)

1. be used for the treatment of an implanted drug delivery medical device for the medical condition relevant with body cavity, described body cavity comprises multilamellar, and described implanted drug delivery medical device comprises:
With the outer surface of multiple nano-carrier coating, described multiple nano-carrier has multiple mean diameter, the nano-carrier of described multiple nano-carrier containing embedding medium around medicine, described embedding medium comprises at least one biological reagent, described nano-carrier there is the mean diameter that is suitable for penetrating at least multilamellar described in one deck and described nano-carrier surface not containing described medicine, described multiple mean diameter comprises that the first mean diameter is 800nm-1500nm, the second mean diameter is 300nm-800nm, the 3rd mean diameter is 10nm-300nm.
2. implanted drug delivery medical device as claimed in claim 1, it is characterized in that, described biological reagent comprises at least one in blood excipient and phospholipid.
3. implanted drug delivery medical device as claimed in claim 1, it is characterized in that, described implanted drug delivery medical device is when the target position of described body cavity, described multiple nano-carrier discharges from described outer surface, and in described multiple nano-carrier at least one nano-carrier through at least one deck in described multilamellar.
4. implanted drug delivery medical device as claimed in claim 1, it is characterized in that, the multilamellar of described body cavity comprises theca interna, middle rete and theca externa.
5. implanted drug delivery medical device as claimed in claim 1, is characterized in that, in described biological reagent, at least one has at least one and is selected from the effect stablized described medicine and the target position of described body cavity is equipped with to affinity.
6. implanted drug delivery medical device as claimed in claim 1, it is characterized in that, described multiple nano-carrier also comprises:
Have the first group of nano-carrier being suitable for the first mean diameter penetrating described body cavity theca interna, wherein when described implanted drug delivery medical device is when the target position of described body cavity, described first group of nano-carrier penetrates described theca interna;
There is second group of nano-carrier of the second mean diameter being suitable for penetrating rete in described body cavity, wherein when described implanted drug delivery medical device is when the target position of described body cavity, described second group of nano-carrier penetrates described middle rete and described theca interna by theca interna and middle rete relevant vascular parietal vessel; With
There is the 3rd group of nano-carrier of the 3rd mean diameter being suitable for penetrating described body cavity theca externa, wherein when described implanted drug delivery medical device is when the target position of described body cavity, described 3rd group of nano-carrier penetrates described theca externa, described theca interna and described middle rete by theca interna and middle rete relevant vascular parietal vessel and theca externa relevant vascular parietal vessel, wherein said 3rd group of nano-carrier in described theca externa accumulation and described medicine discharge from described 3rd group of nano-carrier within a period of time.
7. implanted drug delivery medical device as claimed in claim 1, it is characterized in that, described implanted drug delivery medical device is support, air bag or balloon catheter.
8. implanted drug delivery medical device as claimed in claim 7, it is characterized in that, described implanted drug delivery medical device is the support be contained on air bag.
9. implanted drug delivery medical device as claimed in claim 7, it is characterized in that, described implanted drug delivery medical device is the support be contained on air bag, the described at least partially air bag wherein extending beyond described mount proximal end and the described multiple nano-carrier coating of described at least partially air bag extending beyond described rack far end.
10. implanted drug delivery medical device as claimed in claim 7, it is characterized in that, described support and at least two-layer described multiple nano-carrier coating of described air bag, at least two-layer skin wherein corresponding to described air bag and described support comprises nano-carrier that at least one has the 3rd mean diameter to be released with the prominent of nano-carrier producing described at least one when described air bag expands after the target position of described body cavity and have the 3rd mean diameter.
11. implanted drug delivery medical devices as claimed in claim 10, it is characterized in that, comprise at least one corresponding to the skin of at least two layers described in described support and there is the nano-carrier of described 3rd mean diameter and the internal layer corresponding to described in described support at least two layers comprises at least one has the nano-carrier that the nano-carrier of the second mean diameter and at least one have the first mean diameter, the skin wherein corresponding to described support and air bag produces the nano-carrier that at least one has described 3rd mean diameter and releases from the prominent of outer surface of described support, and at least one nano-carrier wherein with described second mean diameter and at least one nano-carrier with described first mean diameter when the target position of described body cavity within a period of time through at least one deck of described multilamellar.
12. implanted drug delivery medical devices as claimed in claim 10, it is characterized in that, described implanted drug delivery medical device at least two layers of described multiple nano-carrier coating, the skin of wherein said at least two layers comprises at least one medicine, and described medicine is different from least one medicine contained by the internal layer of described at least two layers.
13. implanted drug delivery medical devices as claimed in claim 6, is characterized in that, described first group of nano-carrier, second group of nano-carrier and the 3rd group of nano-carrier comprise different medicines.
14. implanted drug delivery medical devices as claimed in claim 6, is characterized in that, described first group of nano-carrier is containing the medicine being selected from antiinflammatory and antithrombotic agents and described second group of nano-carrier contains antiproliferative.
15. implanted drug delivery medical devices as claimed in claim 6, it is characterized in that, described first group of nano-carrier is containing antiproliferative medicine, and described second group of nano-carrier is containing the medicine being selected from antithrombotic agents and antiinflammatory, and described 3rd group of nano-carrier is containing agent for promoting healing.
16. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, described medicine is selected from lower group: anti-proliferating agent, antiinflammatory, antitumor agent, anticoagulant, anti-fiber agent, antithrombotic agents, antimitotic agent, antibiotic agent, anti-allergic agent and antioxidant, antiproliferative, estrogen, protease inhibitor, antibody, immunosuppressant, cytostatic agent, cytotoxic agent, calcium channel blocker, phosphodiesterase inhibitor, prostaglandin inhibitor, food supplement, vitamin, anti-platelet aggregation agent and genetically engineered epithelial cell.
17. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, described medicine is selected from lower group: paclitaxel, sirolimus, tacrolimus, clobetasol, dexamethasone, genistein, heparin, 17 beta estradiols, rapamycin, everolimus, ethyl rapamycin, Zuo Tamosi, ABT-578, Pai Ermosi A9, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin and derivant thereof, heparin sodium, low molecule weight heparin, heparinoid, hirudin, argatroban, Forskolin, vapiprost, prostacyclin, prostacyclin analogs, dextran, D-phe-pro-arg-chloromethyl ketone, dipyridamole, glycoprotein iib/iiia, lepirudin 023 ludon, bivalirudin, nifedipine, colchicine, lovastatin, sodium nitroprusside, suramin, serotonin blocker, steroid, thiol protease inhibitor, triazolo pyrimidine, nitric oxide or nitric oxide donors, superoxide dismutase, superoxide dismutase mimics, estradiol, aspirin, angiopeptin, captopril, cilazapril, lisinopril, Pemirolast Potassiu, alpha-interferon, with biological activity RGD.
18. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, described biological reagent is selected from lower group: come from the excipient of blood, lipoid, steroid, vitamin, estradiol, esterified fatty acid, non-esterified fatty acid, inositol, Pfansteihl salt, lipoprotein, sugar, calcium phosphate and be derived from the material of people, egg and Semen sojae atricolor.
19. implanted drug delivery medical devices as claimed in claim 18, it is characterized in that, described lipoid is phospholipid.
20. implanted drug delivery medical devices as claimed in claim 18, it is characterized in that, described sugar is glucose.
21. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, in described biological reagent, at least one is dissolved in the medium that pH is less than 7.4.
22. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, described medical condition comprises described endoceliac occluding body lumens.
23. implanted drug delivery medical devices as claimed in claim 1, is characterized in that, described medical condition comprises at least one in the accumulation of described endoceliac restenosis, atherosclerosis and speckle.
24. implanted drug delivery medical devices as claimed in claim 1, it is characterized in that, described body cavity comprises blood vessel.
25. implanted drug delivery medical devices as claimed in claim 24, it is characterized in that, described blood vessel is selected from lower group: coronary artery, peripheral arterial, arteries and veins aroused in interest, iliac artery, inferior genicular artery and vein.
26. implanted drug delivery medical devices as claimed in claim 2, it is characterized in that, described phospholipid is selected from lower group: phosphatidylcholine (lecithin), phosphatidyl glycerol, phosphatidylinositols, Phosphatidylserine, phosphatidic acid and PHOSPHATIDYL ETHANOLAMINE.
27. implanted drug delivery medical devices as claimed in claim 2, it is characterized in that, described phospholipid is selected from lower group: phosphatidylcholine (lecithin), cuorin, phosphatidylinositols, Phosphatidylserine, phosphatidic acid and PHOSPHATIDYL ETHANOLAMINE.
The purposes of the 28. multiple nano-carriers with multiple mean diameter in the implanted drug delivery medical device of the medical condition relevant with body cavity for the preparation for the treatment of, described body cavity comprises multilamellar, wherein said implanted drug delivery medical device is placed in described endoceliac target position, described implanted drug delivery medical device comprises the outer surface of described nano-carrier coating, the nano-carrier of described multiple nano-carrier containing embedding medium around medicine, described embedding medium comprises at least one biological reagent, described nano-carrier there is the mean diameter that is suitable for penetrating at least multilamellar described in one deck and described nano-carrier surface not containing described medicine, described multiple nano-carrier discharges from described implanted drug delivery medical device at described target position, and described multiple mean diameter comprises the first mean diameter is 800nm-1500nm, second mean diameter is 300nm-800nm, 3rd mean diameter is 10nm-300nm.
29. purposes as claimed in claim 28, it is characterized in that, described biological reagent comprises at least one in blood excipient and phospholipid.
30. purposes as claimed in claim 28, it is characterized in that, described implanted drug delivery medical device is support, air bag or balloon catheter.
31. purposes as claimed in claim 30, it is characterized in that, described implanted drug delivery medical device is the support be contained on air bag.
32. purposes as claimed in claim 28, is characterized in that, described implanted drug delivery medical device is support and described support air bag and balloon catheter are placed on described target position.
33. purposes as claimed in claim 32, it is characterized in that, described multiple nano-carrier discharges from described support in 3-45 days after target position in described body cavity at described stentplacement.
34. purposes as claimed in claim 28, is characterized in that, described medical condition is described endoceliac occluding body lumens.
35. purposes as claimed in claim 28, it is characterized in that, described medical condition is selected from lower group: described endoceliac restenosis, atherosclerosis and speckle are accumulated.
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